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Vono et al., Brazil and the
Netherlands, reported on a family where the consanguineous
parents (possibly heterozygous) had three siblings with
congenital goiter and early hypothyroidism with a negative
perchlorate discharge test and high values for early and 24
radioiodine uptake. In spite of the large goiter, serum Tg was
dysproportionally low (3.5 ng/mL) and did not rise after
exogenous TSH stimulation. Thyroid gland tissue was obtained from
two siblings and the Tg mRNA extracted from the specimen. The
complete coding region of 8307 bp was directly sequenced and
revealed a homozygous point mutation: a C to a T transition at
nucleotide position 886 in exon 7. This resulted in a frameshift
with a stopcodon at aminoacid position 277. A Tg cDNA construct
containing the mutation was expressed in a rabbit reticulocyte
lysate resulting in a truncated Tg protein of only 30 kDa. This
truncated protein was apparently still capable of limited thyroid
hormonogenesis characterized by an elevated serum total T3 and
low T4 level in the patients. Moreover, the addition of excess
iodine to their usual diet corrected the hypothyroidism in these
subjects.
Gonzalez and co-authors reported a collaborative study on Pendred’s syndrome (PDS) involving three countries (Mexico, Brazil and the USA). Basically they described the clinical and molecular analysis of three Mexican families with affected individuals with large goiters since early childhood and congenital sensorineural deafness. Thyroid function tests, perchlorate test, RAIU and thyroid scan, audiometry, CT scan and MRI of the auditory organ were performed in all individuals. DNA was extracted from peripheral leukocytes and all 21 exons of the PDS gene were submitted to direct sequence analysis. Haplotvpe analysis was performed using microsatellite markers. Four patients presented with goiter, positive perchlorate test, but without deafness. Two male patients were found to be hypothyroid. The 4 deaf individuals had a Mondini malformation and sensorineural deafness documented by audiometry. TSH was elevated in two individuals. Thyroid scintigraphy documented goitrous enlargement in all six patients and a positive RAI discharge after administration of 1 gram potassium perchlorate. DNA analysis revealed a complex homozygous deletion/insertion mutation in family 3 resulting in a premature stopcodon in codon 137. Haplotype analysis documented identical alleles at the Pendred locus, a finding suggesting a common ancestor. In family 1 the affected individuals were heterozygous for a substitution of alanine 411 by proline (A411P), but no other mutation in the coding region could be detected. In Family 2, a heterozygous substitution of valine 137 by phenylalanine was found in one allele. In conclusion: the finding of two patients with hypothyroidism is unusual for Pendred's syndrome, which is usually associated with normal thyroid hormone levels. Molecular analysis resulted in the identification of three mutations in the PDS gene. Family 3 had a son who was homozygous for a mutation. Only one affected allele was found in the other families suggesting that these patients are compound heterozygotes for mutations in the PDS gene and that the second allele harbors a mutation in coding or regulatory sequences. Nogueira and collaborators, São Paulo, Brazil and Chicago, USA, reported combined pituitary hormone deficiency (CPHD) in an inbred Brazilian kindred. The pituitary hormone deficiency was associated with a mutation in the Prophet of pit 1 (PROP-1) gene. Defects in the development and function of the hypothalamic-pituitary axis can result in various forms of combined pituitary hormone deficiency (CPHD). Patients with CPHD usually present with GH deficiency, and impaired production and secretion of one or several other anterior pituitary hormones (PRL, TSH, LH, FSH, CTH). Inactivating mutations in PROP-1 have been recognized as cause of a more complex autosomal recessive CPHD phenotype which also includes deficiencies of LH and FSH, in addition to the lack of GH, PRL and TSH. PROP-1 is a paired-like homeodomain factor that appears to be involved in ontogenesis, differentiation and function of gonadotropes, somatotropes, lactotropes, and thyrotropes, and it is necessary for Pit-1 expression. The PROP-1 gene is located on chromosome 5q35 and consists of three translated exons with an open reading frame of 678 bp encoding a 226 amino acid protein. The authors described molecular analysis of an inbred Brazilian family with CPHD associated with a PRP-mutation. The parents are first cousins and had thirteen offspring. Clinically, there were no signs of congenital hypothyroidism. The four affected siblings came to medical attention at the age of 7 because of growth retardation, and all affected individuals failed to enter puberty. Detailed endocrine evaluations were performed on two occasions in 1980 and 1990. Siblings II-7 and II-8 had severe hypoplasia of the pituitary gland on MRI imaging, and hypoplastic thyroid glands and ovaries on ultrasonographic evaluation. Direct sequencing of the PROP-1 gene revealed a deletion of two base pairs (A301G302) in exon 2, resulting in a frameshift and a premature stop in codon 109 in the homeodomain. The phenotype associated with the A301G302 truncation appears to affect all anterior pituitary hormones in early childhood in all patients. The clinical characteristics of this family support the notion that this truncation results in a more severe phenotype than missense mutations in the aminoterminal part of the homeodomain. |
